PROTECTIVE ROLE OF HEAT SHOCK PROTEINS IN INSULIN RESISTANCE

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 目前迫切需要了解骨骼肌中热休克蛋白（HSP）的基本抗氧化特性，并建立新的HSP治疗方法来预防胰岛素抵抗。我们的长期目标是阐明导致2型糖尿病发展的肌肉胰岛素抵抗机制。 该特定应用的目的是确定增加的HSP表达可以调节骨骼肌中的应激激酶和胰岛素信号传导途径的程度。我们的中心假设是，增加HSP 72和HSP 25的表达将减少应激激酶的激活，并改善胰岛素信号。我们进一步假设慢性应激激酶激活导致高脂喂养的胰岛素抵抗骨骼肌中HSP表达降低，增加了对氧化应激的易感性。在强有力的初步数据的指导下，这一假设将通过追求两个特定的目标进行测试：1）确定HSP依赖性机制，以改善骨骼肌胰岛素信号传导; 2）确定调节胰岛素抵抗骨骼肌中HSP表达的信号通路。在特定目标1中，我们将确定HSP 72和HSP 25表达的增加是否抑制应激激酶c-jun末端激酶（JNK）和κ B激酶β抑制剂。（IKK β），并改善胰岛素抵抗的Wistar大鼠的饲料喂养和高脂肪喂养的胰岛素信号。在具体目标2中，我们将确定糖原合成酶激酶-3（GSK-3）和JNK信号通路在多大程度上调节胰岛素抵抗骨骼肌中HSP的表达。GSK-3和JNK的药理学抑制剂将用于潜在地改变主要HSP转录因子热休克因子1（HSF-1）的活化。作为所提出的目标的一个结果，我们期望建立一个新的治疗作用，热休克蛋白在对抗胰岛素抵抗和确定的分子机制，调节热休克蛋白在胰岛素抵抗的骨骼肌表达。这项研究意义重大，因为它将有助于建立预防胰岛素抵抗的重要新候选靶点，并增强我们对许多疾病状态下细胞防御能力下降的理解。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. There is a critical need to understand the fundamental antioxidant properties of heat shock proteins (HSPs) in skeletal muscle and establish novel HSP therapies for preventing insulin resistance. Our long-term goal is to elucidate the mechanisms of muscle insulin resistance that lead to the development of type 2 diabetes. The objective of this particular application is to determine the extent to which increased HSP expression can modulate stress kinase and insulin signaling pathways in skeletal muscle. Our central hypothesis is that increased expression of HSP72 and HSP25 will decrease stress kinase activation and improve insulin signaling. We further hypothesize that chronic stress kinase activation results in low HSP expression in high fat-fed insulin-resistant skeletal muscle, increasing susceptibility to oxidative stress. Guided by strong preliminary data, this hypothesis will be tested by pursuing two specific aims: 1) Identify HSP-dependent mechanisms that function to improve skeletal muscle insulin signaling; 2) Identify signaling pathways that modulate HSP expression in insulin-resistant skeletal muscle. In Specific Aim 1, we will determine whether increased expression of HSP72 and HSP25 inhibit the stress kinases c-jun terminal kinase (JNK) and inhibitor of kappa B kinase beta.(IKKbeta), respectively, and improve insulin signaling in chow-fed and high fat-fed, insulin resistant Wistar rats. In Specific Aim 2, we will determine the extent to which glycogen synthase kinase-3 (GSK-3) and JNK signaling pathways modulate HSP expression in insulin-resistant skeletal muscle. Pharmacological inhibitors of GSK-3 and JNK will be used to potentially modify activation of the primary HSP transcription factor, heat shock factor 1 (HSF-1). As an outcome of the proposed aims, we expect to establish a novel therapeutic role for HSPs in combating insulin resistance and identify molecular mechanisms that regulate HSP expression in insulin-resistant skeletal muscle. The proposed research is significant because it will help to establish important new candidate targets for prevention of insulin resistance as well as enhance our understanding of the decline in cellular defenses that occurs with numerous disease states.